Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/18—One oxygen or sulfur atom
  • C07D231/20—One oxygen atom attached in position 3 or 5
  • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to novel N-­[(heterocycle)alkyl]-3,4 (or 4,5)-diaryl-1H-pyrazole-­1-acetamides or propanamides, and the preparation thereof, useful for treating cardiac arrhythmia in mammals.
• Bondavalli et al. disclose N-alkyl carbamates of 1-(2-hydroxyethyl)-3,5-diphenyl-1H-pyrazole as antihypertensive, antiarrhythmic, analgesic, antiinflammatory and hypoglycemic agents. Specifically disclosed are the ethyl, isopropyl, phenyl and 1-naphthyl carbamates.
• European patent application 299,407 published January 18, 1989, discloses an extensive series of 4,5-diaryl-1H-pyrazole-1-alkanamides as antiarrhythmic agents.
• the present invention relates to compounds of the formula Ia or Ib or acid-addition salt thereof wherein R1 is hydrogen or lower-alkyl; R2 and R3 are independently hydrogen, hydroxy, lower-alkyl, lower-alkoxy, lower-alkylamino, lower-alkylamido, lower-alkylsulfonamido, nitro, amino, cyano, or halo; R4 is hydrogen or hydroxy; m is one or two; p is one, two, or three; and A is a five- or six-membered heterocycle, composed of carbon and nitrogen, attached to -(CH2) p - at a carbon, and optionally substituted with a lower-alkyl group.
• Lower-alkyl as used herein describes linear or branched hydrocarbon chains of four or fewer carbon atoms; lower-alkoxy as used herein describes linear or branched alkyloxy substituents containing four or fewer carbon atoms; halogen describes bromine, chlorine or fluorine.
• heterocycles within the scope of the invention are pyrrolidine, piperidine, piperazine, imidazole, pyrrole, pyridine, pyrimidine, pyrazine; N-methyl-pyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N-­methylpiperazine, and N-ethylpiperazine.
• compositions for treating cardiac arrhythmia comprise compounds of the formula I together with pharmaceutically acceptable excipients or diluents as required.
• Processes are described for preparing a compound of formula I which comprise reacting a pyrazole-1-acetate or propanoate ester or a pyrazole-­1-acetic or propanoic acid with an amine.
• R5 is hydrogen or lower-alkyl.
• the lower-alkyl ester preferably a methyl or ethyl ester, of a suitably substituted 3,4- or 4,5-diphenylpyrazole-1-alkanoic acid (II) is reacted with an excess of a primary or secondary amine of formula III at 20° to 150°C., preferably at 90 to 150°C.
• the ester II is preferably reacted with about one equivalent of the amine III in the presence of a tertiary amine, preferably diisopropylethylamine, in an inert solvent.
• the compounds of the invention may be synthesized from the free acids, which can be obtained by hydrolysis of the corresponding esters.
• a suitably substituted 3,4- or 4,5-diphenyl-1H-pyrazole-1-acetic or propanoic acid (IIa or IIb wherein R5 is hydrogen) is activated by procedures well-known in the art, such as reaction with an acid chloride to form a mixed anhydride, reaction with a carbodiimide to form an O-acylisourea, or reaction with carbonyl diimidazole to form an imidazolide.
• the activated acid in an inert solvent is then combined at -20° to 75°C. with a stoichiometric amount or a slight excess of a primary or secondary amine of formula III.
• the ester IIa where R4 is hydrogen and m is one, or IIb where m is one may be synthesized from the appropriately substituted desoxybenzoin by formylation by means of known procedures [Russell et al J . Am . Chem . Soc . 76 , 5714 (1954)] followed by condensation with a hydrazinoacetic acid ester in a suitable solvent, preferably ethanol, at 20° to 100°C, preferably at 25°C.
• a suitable solvent preferably ethanol
• the hydrazinoacetate is preferably used in the form of a mineral acid salt from which the free hydrazine may be liberated in situ by the addition of about one equivalent of a base, preferably pyridine.
• Ester IIa where R4 is hydrogen and m is two or IIb where m is two may be synthesized from the appropriately substituted diaryl pyrazole by a two step procedure comprising reaction with acrylonitrile in the presence of base in an inert solvent at 0°-50°C, preferably at about 20°C, followed by hydrolysis of the nitrile using methanol and hydrogen chloride in an inert solvent at 0° to 30°C and then water at 0-30°C.
• the 4,5-diphenyl ester IIa where R4 is hydrogen may be synthesized from the appropriately substituted desoxybenzoin by a two-step procedure comprising reaction with N,N-dimethylformamide dimethyl acetal in an inert solvent, preferably methyl tert -butyl ether, at 20°-100°C preferably at about 55°C, followed by cyclization with a lower-alkyl ester of hydrazinoacetic acid as described above.
• ester IIa where R4 is hydroxy may be synthesized from the appropriate 3,4-diphenyl-5-pyrazolone by alkylation with an ⁇ -haloalkanoate in the presence of about one equivalent of a base, preferably potassium carbonate, in an inert solvent at 20-100°C, preferably at about 55°C.
• a base preferably potassium carbonate
• the compounds of formulas Ia and Ib are useful both in the free base form and the form of acid-addition salts, and both forms are within the purview of the invention.
• the acid-addition salts are in some cases a more convenient form for use, and in practice the use of the salt form inherently amounts to the use of the base form.
• the acids which can be used to prepare the acid-addition salts include preferably those which produce, when combined with the free base, medicinally acceptable salts that is, salts whose anions are relatively innocuous to the animal organism in medicinal doses of the salts so that the beneficialal properties inherent in the free base are not vitiated by side effects ascribable to the anions.
• hydrochloride, fumarate, toluenesul­fonate, methanesulfonate, or maleate salts are those derived from other mineral acids and organic acids.
• the acid-addition salts of the basic compounds are prepared either by dissolving the free base in aqueous alcohol solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and an acid in an organic solvent, in which case the salt separates directly, is precipitated with a second organic solvent, or can be obtained by concentration of the solution.
• all acid-addition salts are within the scope of the present invention as well as solvates, e. g. hydrates, of the compounds formed. All acid-addition salts are useful as sources of the free base form even if the particular salt per se is desired only as an intermediate product, as, for example, when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in preparing a medicinally acceptable salt by ion exchange procedures.
• the structures of the compounds of the invention were established by the mode of synthesis, by elemental analysis, and by infrared, ultraviolet, nuclear magnetic resonance, and mass spectroscopy. The course of the re­actions and the identity and homogeneity of the products were assessed by thin layer chromatography (TLC) or gas-liquid chromatography (GLC).
• TLC thin layer chromatography
• LLC gas-liquid chromatography
• THF tetrahydrofuran
• DMP N,N-dimethylformamide
• Ac acetyl residue
• Example 2 Chromatography of the mother liquors from Example 1A on silica gel using 1:1 chloroform-hexane provided up to 20% of the 3,4-­diphenyl isomer.
• the 3,4-diphenyl isomer (Example 2) may be distinguished from the 4,5-diphenyl isomer (Example 1) by its higher Rf on TLC.
• An analytical sample may be obtained by distillation at 0.2 mm, boiling range 186-189°C.
• the iminoether hydrochloride was dissolved in 5 mL of methylene chloride, cooled to 0°C, and 10 drops of water were added. The reaction was stirred for a few minutes at 0° C and then for a few minutes at room temperature. The methylene chloride layer was separated and dried over magnesium sulfate, filtered and evaporated to yield 30 mg of methyl 4,5-diphenyl-1H-pyrazole-1-propanoate,mp 72-74°C.
• the 2-(4-cyanophenyl)-1-phenylethanone was synthesized from 4-cyanobenzyl bromide and -cyano-N,N-diethylbenzenemethanamine: 3.95g (0.16mol) of sodium hydride was suspended in 80mL of DMF under nitrogen and 29.9g (0.16mol)of the methanamine in 20 mL of DMF was added dropwise. When evolution of hydrogen had ceased, 31.2g (0.16mol) of the benzyl bromide in 30mL of toluene was added and the reaction stirred 3 hr at room temperature.
• the water layer was made basic with solid sodium carbonate and the product extracted into methylene dichloride, dried over sodium sulfate and stripped.
• the product was purified by chromatography on silica gel eluting with 5% triethylamine in chloroform. The purified product was crystallized from acetone as the fumarate salt and was recrystallized from ethanol to yield 8.56 of product, mp 179-180°C.
• N-methyl-N-[2-(1-piperidinyl)ethyl]-­4,5-diphenyl-1H-pyrazole-1-propanamide may be synthesizied from methyl 4,5-diphenyl-1H-pyrazole-1-propanoate of example 4 and 1-­[2-(methylamino)ethyl]piperidine.
• 4-(4-chlorophenyl)-N-[(1-methyl-3-piperidinyl)methyl]-­5-phenyl-1H-pyrazole-1-acetamide may be synthesized from ethyl 4-(4-chlorophenyl)-5-phenyl-1H-pyrazole-1-acetate of example 9 and 1-methyl-3-piperidinemethanamine.
• 5-[4-(dimethylamino)phenyl]-4-phenyl-­N-[(3-pyridinyl)methyl]-1H-pyrazole-1-acetamide may be synthesized from ethyl 5-[4-(dimethylamino)phenyl]-4-phenyl-1H-pyrazole-1-­acetate of example 11 and 3-(aminomethyl)pyridine.
• Fractions 50-65 contained the O-alkylated product; fractions 75-79 provided1.1g of the desired N-alkylated product, mp 181 - 183°C.
• N-(1-ethyl-4-piperidinyl)-3-hydroxy-4,5-diphenyl-­1H-pyrazole-1-acetamide may be synthesized from ethyl 3-hydroxy-­4,5-diphenyl-1H-pyrazole-1-acetate of example 25 and 1-ethyl-­4-piperidinamine.
• Time intervals between aconitine injection and the appearance of arrhythmias were determined. Specifically noted was the time until the onset of (i) the first premature ventricular contraction (PVC); (ii) the first sustained run of ventricular tachycardia consisting of 10 or more ventricular beats (VTACH); and (iii) the time until the appearance of ventricular fibrillation lasting longer than 15 seconds (VFIB).
• PVC premature ventricular contraction
• VTACH first sustained run of ventricular tachycardia consisting of 10 or more ventricular beats
• VFIB the time until the appearance of ventricular fibrillation lasting longer than 15 seconds
• the average time and standard error of the mean until the appearance of these arrhythmias were calculated for each treatment group and compared to concurrent controls using a one-way analysis of variance. Activity was defined as a statistically significant delay in the onset of PVC, VTACH and VFIB time course compared to control values.
• the compounds of the invention can be prepared for use by conventional pharmaceutical procedures: that is, by dissolving or suspending them or their pharmaceutically acceptable salts in a pharmaceutically acceptable vehicle, e.g., water, aqueous alcohol, glycol, oil solution or oil-water emulsion, for parenteral or oral administration;or by incorporating them in unit dosage form as capsules or tablets for oral administration either alone or in combination with conventional adjuvants or excipients, eg., calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia, and the like.
• a pharmaceutically acceptable vehicle e.g., water, aqueous alcohol, glycol, oil solution or oil-water emulsion
• conventional adjuvants or excipients eg., calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia, and the like.
• the percentage of active component in the composition and method for treating or preventing arrhythmia can be varied so that a suitable dosage is obtained.
• the dosage administered to a particular patient is variable depending upon the clinician's judgement using as the criteria: the route of administration, the duration of treatment, the size and condition of the patient, the potency of the active component, and the patient's response thereto.
• An effective dosage amount of active component can thus be determined by the clinician considering all criteria and utilizing his best judgement on the patient's behalf.

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• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Cardiology (AREA)
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Citations (3)

• 1989
  • 1989-03-22 US US07/327,218 patent/US4898880A/en not_active Expired - Fee Related
• 1990
  • 1990-02-28 NZ NZ232724A patent/NZ232724A/en unknown
  • 1990-03-02 EP EP90104124A patent/EP0388690A1/en not_active Withdrawn
  • 1990-03-02 IL IL93613A patent/IL93613A0/xx unknown
  • 1990-03-06 FI FI901126A patent/FI901126A0/fi not_active Application Discontinuation
  • 1990-03-13 NO NO90901169A patent/NO901169L/no unknown
  • 1990-03-14 AU AU51320/90A patent/AU621997B2/en not_active Expired - Fee Related
  • 1990-03-14 MY MYPI90000404A patent/MY105594A/en unknown
  • 1990-03-15 KR KR1019900003475A patent/KR900014325A/ko not_active Application Discontinuation
  • 1990-03-16 PT PT93467A patent/PT93467A/pt not_active Application Discontinuation
  • 1990-03-16 JP JP2066756A patent/JPH02286663A/ja active Pending
  • 1990-03-21 CA CA002012655A patent/CA2012655A1/en not_active Abandoned

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